摘要
目的通过单细胞转录组联合蛋白质组学分析,结合体内外实验,探索调节肝细胞癌进展的新颖机制,为肝细胞癌治疗提供新策略。方法利用R语言对公开数据库中肝癌患者单细胞转录组及细胞模型蛋白质组数据进行重分析,筛选响应肝细胞癌微环境变化的关键细胞亚群,并结合小鼠皮下荷瘤模型及肿瘤细胞共培养,验证该细胞群体对肝细胞癌微环境的调控作用。结果通过生物信息学分析发现肝癌微环境中巨噬细胞与细胞外基质的相互作用与肿瘤进展密切相关;体内及体外实验证实肿瘤相关巨噬细胞相较于非肿瘤浸润的巨噬细胞,与细胞外基质的主要成分胶原蛋白存在更强的相互作用;在荷瘤小鼠模型中,利用BAPN药物解聚细胞外基质,肿瘤生长受限,表现为肿瘤僵硬度降低、血管生成受抑制、骨髓来源抑制性细胞浸润减少(P<0.05)。结论巨噬细胞-细胞外基质互作在调节肝癌微环境中发挥重要作用,靶向肿瘤细胞外基质重构或可成为肝细胞癌实体肿瘤治疗的新策略。
Objective To explore novel mechanisms regulating the progression of hepatocellular carcinoma(HCC)and to provide new therapeutic strategies for HCC through single-cell transcriptomics,proteomics and in vivo and in vitro experiments.Methods We reanalyzed single-cell transcriptomic and proteomic data of HCC obtained from public database using R package.Key cell subpopulations that respond to the HCC microenvironment were identified.The regulatory effects of these cell subpopulations on the HCC progression were validated in mouse subcutaneous tumor-bearing model and in-vitro system.Results Bioinformatic analysis revealed that the interaction between macrophages and the extracellular matrix(ECM)in the HCC microenvironment was closely related to tumor progression.In vivo and in vitro experiments confirmed that the tumor-associated macrophages exhibited stronger interactions with collagens,a major component of the ECM,compared to non-tumor-infiltrating macrophages.In a tumor-bearing mouse model,injection of BAPN to depolymerize ECM inhibited tumor growth,reduced tumor stiffness,suppressed angiogenesis,and decreased infiltration of bone marrow-derived suppressive cells(P<0.05).Conclusion The interaction between macrophages and ECM plays a critical role in regulating the HCC microenvironment.Targeting the tumor ECM may serve as a new strategy for the treatment of HCC.
作者
王谨
朱娟娟
杨芳芳
WANG Jin;ZHU Juanjuan;YANG Fangfang(Beijing Key Laboratory of Emerging Infectious Diseases,Institute of Infectious Diseases,Beijing Ditan Hospital,Capital Medical University,Beijing 100015,China;不详)
出处
《河北医药》
CAS
2024年第18期2725-2731,共7页
Hebei Medical Journal
基金
国家自然科学基金青年项目(编号:32300658)
北京市医院管理中心创新梦工场(编号:202105)。
关键词
肝细胞癌
单细胞测序
蛋白质组
肿瘤相关巨噬细胞
细胞外基质
hepatocellular carcinoma
single-cell RNA sequencing
proteomics
tumor associated macrophages
extracellular matrix
